Recent studies suggest that the majority of HIV infected patients develop mild or asymptomatic neurocognitive dysfunction despite being aviremic on antiretroviral therapy. Coupled with the observation that the viral burden in the brain may be much larger than previously anticipated, the possibility that small amounts of viral products over extended periods of time may directly cause neuronal dysfunction needs to be considered. One of these viral proteins, Tat is particularly attractive since its production and release from HIV-infected cells is not impacted by currently available antiretroviral agents. Substantial amount of data from our laboratory over the last 15 years clearly shows that Tat interacts directly with the NMDA receptors to cause neuronal injury. Over the previous five years of funding we further characterized the mechanisms of Tat-mediated neuronal injury and discovered that the mechanism of excitation of the NMDA receptor by Tat is unlike any other known agonist. To further characterize these interactions we will use a combination of in vitro and in vivo models to determine the role of Tat-NMDA receptor interactions in mediating synaptodendritic injury and using molecular studies including crystallography we will determine the exact molecular basis of these protein-protein interactions. We anticipate that these studies will not only have important implications for understanding the pathophysiology of HIV associated neurocognitive disorders but will also advance our understanding of the physiological and pathological states in which the NMDA receptor plays a role. The grant application will examine three specific aims: Aim 1: To characterize the post-translational modifications and essential residues of Tat that mediates its neurotoxic properties. Aim 2: To determine the role of Tat-NMDA receptor interaction in mediating synaptodendritic injury Aim 3: To determine the structural basis of the interactions between Tat and the NMDA receptor.